Two mutated HEXA alleles in a Druze patient with late-infantile Tay- Sachs disease

Two affected HEXA alleles were found in an Israeli Druze Tay-Sachs child born to first-cousin parents. His paternal allele contained two adjacent changes in exon 5: Δ496C, which resulted in a frameshift and premature termination codon 96 nucleotides downstream, and 498C→G, a silent mutation. The maternal allele had a 835T→C transition in exon 8 (S279P). Phosphoimaging quantitation of the parents' RNAs showed that the steady- state levels of mRNAs of the mutant exons 5 and 8 were 5% and 50%, respectively, of normal levels. The exon 5 mutated allele with the premature translation termination resulted in severe deficiency of Hex A. Transient expression of the exon 8 mutated α-chain cDNA in COS-1 cells resulted in deficiency of enzymatic activity. The child exhibited a late-infantile-type disease.